The most promising new therapies for FTLD will target specific proteins that are associated with the majority of FTLD cases: tau and TAR DNA binding protein 43 (TDP-43). A challenge for conducting clinical trials with such agents is the inability to predict the underlying pathology in the majority of FTLD cases who do not carry a known causative mutation. Of these sporadic cases, the strongest clinical-pathological association for underlying tau pathology is for Progressive Supranuclear Palsy syndrome (PSPS). For TDP-43 pathology, the strongest associations are for semantic variant Primary Progressive Aphasia (svPPA) and frontotemporal dementia with amyotrophic lateral sclerosis (FTD-ALS). The major goal of this research project is to determine the barriers to clinical trial enrollment in these syndromes to create a wellcharacterized cohort of clinical trial-eligible FTLD patients with predictable underlying pathology. Recent evidence also suggests that systemic inflammation due to imbalances in Tumor Necrosis Factor alpha (TNFa) signaling may play a role in tDP-43 FTLD. This cross-sectional study will recruit 650 svPPA, FTD-ALS and PSPS patients from the online FTLD CRC patient registry who will be evaluated at the nearest FTLD CRC clinical site, or from patients already followed at these sites. All individuals will undergo a diagnostic evaluation by an expert FTLD CRC investigator including genotyping for known FTLD-causing mutations, a new FTLD-specific assessment battery (the FTLD Module), as well as questionnaires assessing quality of life and factors that affect clinical trial eligibility. In addition, plasma cytokine levels will be measured using a standard multiplexed ELISA assay to assess whether anti-TNF-alpha drugs should be pursued as a potential treatment for svPPA and FTD-ALS. We aim to: 1) estimate the achievable sample sizes and identify the most important barriers to clinical trial participation for key the sporadic FTLD clinical trial populations, svPPA, FTD-ALS and PSPS; 2) determine the percentage of sporadic svPPA, FTD-ALS and PSPS patients who carry known FTLD-associated mutations; 3) examine the association between autoimmune disease and pro-inflammatory cytokine levels and svPPA, FTD-ALS and PSPS.